Intracellular Growth of Legionella Pneumophila

这项提案的长期目标是了解革兰氏阴性细菌病原体嗜肺军团菌如何能够在正常杀菌的吞噬细胞内生存和复制。这笔赠款将集中于确定嗜肺乳杆菌如何改变内吞途径并阻止宿主细胞的吞噬小体-溶酶小体融合。其具体目的是通过研究两种关键的Dot蛋白DotB和DotL在Dot/ICM复合体的组装和活性中的作用来表征Dot结构，并确定该复合体输出到巨噬细胞宿主细胞的底物(S)。这项提议与健康有关有两个方面。首先，建立L使用的在巨噬细胞内生存和复制的机制将为进一步了解它是如何致病的，并可能揭示用于药物治疗的新靶点。其次，由于各种细菌病原体通常使用专门的分泌系统，因此关于嗜肺乳杆菌分泌器的知识可能适用于了解其他病原体使用的毒力分子机制，并可作为预防或治疗许多不同疾病的基础。

The long term objective of this proposal is to understand how a Gram negative bacterial pathogen, Legionella pneumophila, is able to survive and replicate inside normally bactericidal phagocytic cells. This grant will focus on determining how L. pneumophila alters the endocytic pathway and prevents phagosome-lysosome fusion of host cells. The specific aims are to characterize the Dot apparatus by examining the role of two critical Dot proteins, DotB and DotL, in the assembly and activity of the Dot/Icm complex and to identify the substrate(s) exported by this complex into the macrophage host cell. The health relatedness of this proposal is two fold. First, establishing the mechanism used by L, pneumophila to survive and replicate inside macrophages will provide additional insight into how it causes disease and may reveal novel targets to be used for drug therapy. Second, since specialized secretion systems are commonly used by a variety of bacterial pathogens, knowledge gained about the L. pneumophila secretion apparatus is likely to be applicable to understanding the molecular mechanisms of virulence used by other pathogens, and could serve as the basic to prevent or treat a number of different disease.